Pomalidomide After Combination Chemotherapy in Treating Patients With Newly Diagnosed Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome
Acute Myeloid Leukemia
Chronic Myelomonocytic Leukemia-2
Previously Treated Myelodysplastic Syndrome
Untreated Adult Acute Myeloid Leukemia
Drug: Daunorubicin Hydrochloride
Drug: Idarubicin Hydrochloride
Other: Laboratory Biomarker Analysis
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Pomalidomide Given at the Time of Lymphocyte Recovery Following Induction Timed Sequential Chemotherapy With Cytarabine, Daunorubicin and Etoposide (AcDVP16) in Patients With Newly Diagnosed Acute Myeloid Leukemia (AML) and High-Risk MDS|
- MTD of pomalidomide, defined as the highest dose at which 0 or 1 dose-limiting toxicities (DLT) are observed in 6 patients according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0 [ Time Frame: Up to 21 days ] [ Designated as safety issue: Yes ]The proportion of DLTs at each dose level will be reported with exact binomial 95% confidence intervals. Adverse events will be summarized by dose level for all doses. All toxicities by type and grade will be reported.
- Overall survival [ Time Frame: Time of enrollment onto this study to the time of death, assessed up to 2 years ] [ Designated as safety issue: No ]Standard life table methods will be used to analyze overall survival.
- Progression-free survival (PFS) [ Time Frame: Time from start of treatment to time of progression or relapse or death, assessed up to 2 years ] [ Designated as safety issue: No ]Standard life table methods will be used to analyze PFS. One-year and median PFS with 95% confidence intervals will be reported.
- Proportion of patients achieving CR, CRi, or PR [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]The proportion of patients achieving each category of response will be reported with 95% exact binomial confidence intervals.
- Proportion of toxicities in the expansion cohort graded according to NCI CTCAE version 4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]The proportion of toxicities by type and grade in the expansion cohort will be reported with exact binomial 95% confidence intervals.
- Change in level of cereblon expression in AML cells and sorted T cells [ Time Frame: Baseline to up to 1 year ] [ Designated as safety issue: No ]
- Change in levels of antigen-specific CD8+ T cell responses [ Time Frame: Baseline to up to 1 year ] [ Designated as safety issue: No ]McNemar's test will be used to compare proportions with positive tumor specificity before and after pomalidomide treatment. Sensitivity and specificity of induction responses for predicting CR status will be estimated.
- Change in lymphocyte subpopulations [ Time Frame: Baseline to up to 1 year ] [ Designated as safety issue: No ]Boxplots and line plots will be used to visual trends in the lymphocyte subpopulations. Changes and percentage changes in variables will be summarized. 95% confidence intervals will be obtained by exponentiating the endpoints of confidence intervals for the differences of mean logarithms. A regression model using generalized estimating equations or mixed model used to assess T cell changes. Association of bone marrow and peripheral blood measurements assessed using scatterplots and Spearman's rank correlation coefficients.
- Presence of MRD-leukemic stem cells (LSC) in marrow [ Time Frame: Day 14 ] [ Designated as safety issue: No ]Presence or absence of MRD on day 14 will be correlated with MRD following induction pomalidomide. McNemar's test will be used to compare proportions. Presence or absence of residual LSCs immediately following induction will be correlated with PFS using the Kaplan-Meier survival method.
|Study Start Date:||December 2013|
|Primary Completion Date:||September 2016 (Final data collection date for primary outcome measure)|
Experimental: Treatment (combination chemotherapy, pomalidomide)
See Detailed Description
Other Names:Drug: Daunorubicin Hydrochloride
Other Names:Drug: Etoposide
Other Names:Drug: Idarubicin Hydrochloride
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesDrug: Pomalidomide
I. To define the maximum tolerated dose (MTD) of pomalidomide when given at the time of early lymphocyte recovery following intensive induction timed sequential therapy (TST) with cytosine arabinoside (cytarabine), daunorubicin (daunorubicin hydrochloride) and etoposide (AcDVP-16) in patients with newly diagnosed intermediate- and poor-risk acute myeloid leukemia and high-risk myelodysplastic syndrome (MDS).
II. To evaluate the safety, tolerability and toxicity of pomalidomide given at the time of early lymphocyte recovery following induction AcDVP-16 chemotherapy in adults with newly diagnosed intermediate- and poor-risk acute myeloid leukemia and high-risk MDS.
I. To evaluate the safety, tolerability and toxicity of pomalidomide given as a continuation therapy following induction and/or consolidation chemotherapy in adults with newly diagnosed intermediate- and poor-risk acute myeloid leukemia and high-risk MDS.
II. To document responses (complete remission [CR], CR with incomplete count recovery [CRi], partial remission [PR]) to AcDVP-16 followed by pomalidomide at the time of lymphocyte recovery in newly diagnosed adults with intermediate- and poor-risk acute myeloid leukemia (AML) and high-risk MDS, including duration of response, disease-free and overall survival.
III. Correlative pharmacodynamics studies: a) to characterize the effects of pomalidomide on the functional dynamics of different lymphocyte subpopulations (effector T [Teff], regulatory T [Treg], natural killer [NK] cells) and its impact on tumor-associated antigen (TAA)-specific T cell immunity when given following induction and as a maintenance; b) to examine for the presence of minimal residual disease (MRD) before and after pomalidomide administration during induction and continuation therapy; c) to examine cereblon expression in primary leukemia cells at diagnosis and in sorted T cells prior to and after pomalidomide treatment.
OUTLINE: This is a dose-escalation study of pomalidomide.
INDUCTION: Patients receive cytarabine intravenously (IV) continuously and daunorubicin hydrochloride IV on days 1-3 (patients may otherwise receive idarubicin hydrochloride IV over 10-15 minutes on days 1-3 if daunorubicin hydrochloride is unavailable), and etoposide IV over 3 hours on days 8-10. At the time of early lymphocyte recovery (after day +14), patients also receive pomalidomide orally (PO) for 10-21 days.
CONSOLIDATION: Patients achieving CR or CRi receive cytarabine based treatment at the discretion of the treating investigator, with possible regimens comprising cytarabine IV continuously on days 1-3, and 10-12 and daunorubicin hydrochloride IV on days 1-3, or high- or medium-dose cytarabine IV every 12 hours on days 1, 3, and 5 for 1-4 courses.
CONTINUATION: Patients achieving CR or CRi who did not undergo allogeneic stem cell transplant receive pomalidomide PO daily on days 1-21 beginning 6 weeks following blood count recovery. Treatment repeats every 4-6 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 2 years.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02029950
|United States, Connecticut|
|New Haven, Connecticut, United States, 06520|
|United States, Maryland|
|Johns Hopkins University/Sidney Kimmel Cancer Center|
|Baltimore, Maryland, United States, 21287|
|United States, North Carolina|
|UNC Lineberger Comprehensive Cancer Center|
|Chapel Hill, North Carolina, United States, 27599|
|Principal Investigator:||Ivana Gojo||Johns Hopkins University/Sidney Kimmel Cancer Center|